Epigenetic mechanisms act at the interface between genetics and environment and are an important determinant in disease risk to complex human diseases such as cancer or autism. This proposal employs a combination of systems and approaches that focus on the central question of the impact of persistent environmental pollutants (POPs) on precise epigenetic changes that occur in neurodevelopmental disorders. The widespread prevalence of POPs such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the environment and their detection in human milk has prompted concern about in utero and early infant exposure to these compounds. Perinatal exposure to PCBs and PBDEs in rats results in long-lasting defects in learning, memory, behavior, and seizure susceptibility in adulthood. Epigenetic changes to the genome as a result of PCB and PBDE exposures have not been previously explored but are a plausible explanation for the long-lasting effects on neuropsychological function. This proposal will focus specifically on two compounds, PCB 95 and PBDE 47, with high levels in humans and known effects on neurodevelopment. The genetically controlled component of the proposed studies will be to use a genetically engineered Mecp2 mutant mouse model of Rett syndrome and autism. In additional to animal studies, human blood and post-mortem brain samples from individuals with autism, mental retardation, and controls will be tested for precise epigenetic changes in three neurodevelopmentally important genes (MECP2, GABRB3, UBE3A). Since PCB and PBDE levels will be determined in these human samples, correlations of exposures to epigenetic changes can be performed. Several public health relevant questions will be addressed by these studies: What specific epigenetic changes to neurodevelopmentally important genes occur as a result of POP exposure? What is the compounding effect of known genetic and environmental factors in the etiology of autism and mental retardation? Can specific epigenetic changes be diagnostic for autism and mental retardation of unknown genetic etiology? Are epigenetic changes affecting neurodevelopment heritable?